Gardiquimod: A Toll-Like Receptor-7 Agonist That Inhibits HIV Type 1 Infection of Human Macrophages and Activated T Cells

Buitendijk, Maarten; Eszterhas, Susan K.; Howell, Alexandra L.

doi:10.1089/aid.2012.0313

Cited by 30 publications

(33 citation statements)

References 48 publications

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“…Some novel methods and therapeutic strategies that can overcome viral latency have been developed such as HDAC, disulfiram, galectin-9, ingenol-3-angelate, prostratin, 5-azadC, bryostatin-1, and Runx1 [100, 101]. TLR7/8 agonists induce production of IFN-α that effectively inhibits HIV-1 replication in activated lymphocytes, macrophages or latently infected monocytic cell lines [102, 103]. Because HIV eradication is not achieved by highly active antiretroviral therapy, a strong rationale to investigate the curative potential of IFN-α is needed.…”

Section: Current Potential Applications Of Type I Ifn Classesmentioning

confidence: 99%

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

Gong

Zhao

et al. 2018

Cell Physiol Biochem

139

111

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The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

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Section: Current Potential Applications Of Type I Ifn Classesmentioning

confidence: 99%

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

Gong

Zhao

et al. 2018

Cell Physiol Biochem

139

111

View full text Add to dashboard Cite

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“…These include the TLR7/8 agonist gardiquimod, which has been shown to induce the IFN-α that effectively inhibits HIV-1 replication in vitro in activated lymphocytes and macrophages at concentrations that activate TLR7 but not TLR8 (15). Activation of TLR7/8-mediated signaling pathways upon treatment with either single-stranded RNA or the small molecule TLR7/8 agonist resiquimod (R-848) greatly reduced the ability of lymphoid tissue to support HIV infection, with the stage of anti-HIV action likely to be after virus-host cell membrane fusion but before DNA integration into the host genome.…”

Section: Introductionmentioning

confidence: 99%

TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

Bam

Hansen

Irrinki

et al. 2017

Antimicrob Agents Chemother

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GS-9620 is a potent and selective oral Toll-like receptor 7 (TLR7) agonist that directly activates plasmacytoid dendritic cells (pDCs). GS-9620 suppressed hepatitis B virus (HBV) in animal models of chronic infection and transiently activated HIV expression ex vivo in latently infected peripheral blood mononuclear cells (PBMCs) from virally suppressed patients. Currently, GS-9620 is under clinical evaluation for treating chronic HBV infection and for reducing latent reservoirs in virally suppressed HIV-infected patients. Here, we investigated the in vitro anti-HIV-1 activity of GS-9620. GS-9620 potently inhibited viral replication in PBMCs, particularly when it was added 24 to 48 h prior to HIV infection (50% effective concentration = 27 nM). Depletion of pDCs but not other immune cell subsets from PBMC cultures suppressed GS-9620 antiviral activity. Although GS-9620 was inactive against HIV in purified CD4+ T cells and macrophages, HIV replication was potently inhibited by conditioned medium derived from GS-9620-treated pDC cultures when added to CD4+ T cells prior to infection. This suggests that GS-9620-mediated stimulation of PBMCs induced the production of a soluble factor(s) inhibiting HIV replication in trans. GS-9620-treated PBMCs primarily showed increased production of interferon alpha (IFN-α), and cotreatment with IFN-α-blocking antibodies reversed the HIV-1-inhibitory effect of GS-9620. Additional studies demonstrated that GS-9620 inhibited a postentry event in HIV replication at a step coincident with or prior to reverse transcription. The simultaneous activation of HIV-1 expression and inhibition of HIV-1 replication are important considerations for the clinical evaluation of GS-9620 since these antiviral effects may help restrict potential local HIV spread upon in vivo latency reversal.

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“…The TLR7/8 agonist R848 has been found to induce a block to HIV-1 replication in monocytes and MDMs [7, 8, 10]. To further investigate the mechanism by which the drug interferes with HIV-1 replication we used a VSV-G-pseudotyped reporter virus engineered to package the SIVmac accessory protein Vpx [36].…”

Section: Resultsmentioning

confidence: 99%

“…Buitendijk et al [7] demonstrated that TLR7 and TLR8 activation inhibit HIV-1 replication. Treatment of MDMs with the TLR7 agonist gardiquimod induced a block to infection of co-cultured, activated PBMC and treatment of activated PBMC with agonists specific for TLRs 3, 7, 8 and 9 blocked HIV-1 replication [10].…”

Section: Discussionmentioning

confidence: 99%

“…Several TLR agonists inhibit the replication of HIV-1 in lymphocytes, monocytes and monocyte-derived macrophages (MDM). The imidazoquinoline TLR7/8 agonists R848 (resiquimod) and gardiquimod were found to inhibit HIV-1 replication in MDMs by inducing soluble antiviral factors and in the case of gardiquimod, by acting as a nucleoside reverse transcriptase inhibitor [7, 8]. In monocytes isolated from HIV-infected individuals, R848-treatment reduced viral RNA in the culture supernatants [9].…”

Section: Introductionmentioning

confidence: 99%

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TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes

et al. 2016

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BackgroundMonocytes, the primary myeloid cell-type in peripheral blood, are resistant to HIV-1 infection as a result of the lentiviral restriction factor SAMHD1. Toll-like receptors recognize microbial pathogen components, inducing the expression of antiviral host proteins and proinflammatory cytokines. TLR agonists that mimic microbial ligands have been found to have activity against HIV-1 in macrophages. The induction of restriction factors in monocytes by TLR agonist activation has not been well studied. To analyze restriction factor induction by TLR activation in monocytes, we used the imidazoquinoline TLR7/8 agonist R848 and infected with HIV-1 reporter virus that contained packaged viral accessory protein Vpx, which allows the virus to escape SAMHD1-mediated restriction. ResultsR848 prevented the replication of Vpx-containing HIV-1 and HIV-2 in peripheral blood mononuclear cells and monocytes. The block was post-entry but prior to reverse transcription of the viral genomic RNA. The restriction was associated with destabilization of the genomic RNA molecules of the in-coming virus particle. R848 treatment of activated T cells did not protect them from infection but treated monocytes produced high levels of proinflammatory cytokines, including type-I IFN that protected bystander activated T cells from infection.ConclusionThe activation of TLR7/8 induces two independent restrictions to HIV-1 replication in monocytes: a cell-intrinsic block that acts post-entry to prevent reverse transcription; and a cell-extrinsic block, in which monocytes produce high levels of proinflammatory cytokines (primarily type-I IFN) that protects bystander monocytes and T lymphocytes. The cell-intrinsic block may result from the induction of a novel restriction factor, which can be termed Lv5 and acts by destabilizing the in-coming viral genomic RNA, either by the induction of a host ribonuclease or by disrupting the viral capsid. TLR agonists are being developed for therapeutic use to diminish the size of the latent provirus reservoir in HIV-1 infected individuals. Such drugs may both induce latent provirus expression and restrict virus replication during treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0316-3) contains supplementary material, which is available to authorized users.

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Gardiquimod: A Toll-Like Receptor-7 Agonist That Inhibits HIV Type 1 Infection of Human Macrophages and Activated T Cells

Cited by 30 publications

References 48 publications

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells

TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes

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